Breakout character of islet amyloid polypeptide hydrophobic mutations at the onset of type-2 diabetes

Abstract

Toxic fibrillar aggregates of Islet Amyloid PolyPeptide (IAPP) appear as the physical outcome of a peptidic phase-transition signaling the onset of type-2 diabetes mellitus in different mammalian species. In particular, experimentally verified mutations on the amyloidogenic segment 20-29 in humans, cats and rats are highly correlated with the molecular aggregation propensities. Through a microcanonical analysis of the aggregation of IAPP_{20-29} isoforms, we show that a minimalist one-bead hydrophobic-polar continuum model for protein interactions properly quantifies those propensities from free-energy barriers. Our results highlight the central role of sequence-dependent hydrophobic mutations on hot spots for stabilization, and so for the engineering, of such biological peptides.